Stimulus-Responsive Degradable Polylactide-Based Block Copolymer

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Review

Stimuli-responsive degradable polylactide-based block copolymer nanoassemblies for controlled/enhanced drug delivery Kamaljeet K. Bawa, and Jung Kwon Oh Mol. Pharmaceutics, Just Accepted Manuscript • Publication Date (Web): 11 May 2017 Downloaded from http://pubs.acs.org on May 12, 2017

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Molecular Pharmaceutics

Stimuli-responsive degradable polylactide-based block copolymer nanoassemblies for controlled/enhanced drug delivery Kamaljeet K. Bawa, Jung Kwon Oh* Department of Chemistry and Biochemistry, Concordia University, Montreal, Quebec, Canada H4B 1R6 E-mail: [email protected]

Abstract Polylactide (PLA) is biocompatible and FDA-approved for clinical use and thus has been a choice of the materials valuable for extensive applications in biomedical fields. However, conventionallydesigned PLA-based amphiphilic block copolymer nanoassemblies exhibit slow and uncontrolled release of encapsulated drugs because of the slow biodegradation of hydrophobic PLA in physiological conditions. To improve potentials for clinical use and commercialization of conventional PLA-based nanoassemblies, stimuli-responsive degradation (SRD) platform has been introduced into the design of PLA-based nanoassemblies for enhanced/controlled release of encapsulated drugs. This review summarizes recent strategies that allows for the development of PLA-based ABPs and their selfassembled nanostructures exhibiting SRD-induced enhanced drug release. The design, synthesis, and evaluation of the nanoassemblies as intracellular drug delivery nanocarriers for cancer therapy are focused. Further, the outlook is briefly discussed on the important aspects for the current and future development of more effective SRD PLA-based nanoassemblies toward tumor-targeting intracellular drug delivery.

Abbreviation: PLA: Polylactide; SRD: stimuli responsive degradation; DDS: drug delivery system; ABP: amphiphilic block copolymer; PCL: polycaprolactone; PGA: polyglycolide; ROP: ring opening polymerization; LA: lactide; PEG: poly(ethylene glycol); PNIPAM: poly(N-isopropyl acrylamide); LCST: lower critical solution temperature; SL-SRD: single location stimuli responsive degradation; CCM: core crosslinked micelles; DL-SRD: dual-location stimuli responsive degradation; ML-MSRD: multi-multiple location stimuli responsive degradation; Sn(II)EH2: tin(II) 2-ethylhexanoate; ATRP: atom transfer radical polymerization; CMC: critical micellar concentration; DOX: doxorubicin; GSH: glutathione; DTT: dithiothreitol; THP: tetrahydropyran; PAE: poly(β-amino ester); CLSM: confocal laser scanning microscopy; CYC: cyclopamine; FRET: fluorescence resonance energy transfer

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1. Introduction Polymer-based drug delivery systems (DDS) have been extensively explored as a promising platform in pharmaceutical science and medicine for the transportation of therapeutics to targeted diseased sites. Anticancer therapeutics as small drugs or macromolecules (therapeutic proteins and nucleic acids such as DNA and RNA) are either covalently conjugated to polymeric chains or physically encapsulated inside DDS. This feature can improve the biodistribution of encapsulated therapeutics, thus enhancing therapeutic efficacy while minimizing undesirable side effects common to small drugs.1-6 Among numerous examples of typical polymer-based DDS, self-assembled micellar aggregates have gained significant attention as promising candidates as effective polymer-based DDS.7-10 The micelles are generally formed by aqueous micellization through self-assembly of amphiphilic block copolymers (ABPs) in aqueous solution. They consist of a hydrophobic core, capable of encapsulating a variety of bioactive molecules including anticancer drugs, surrounded with hydrophilic coronas, ensuring colloidal stability and biocompatibility.11-13 Upon intravenous injection into blood stream, drug-loaded micellar nanoassemblies (or nanocarriers) are circulated in the blood to target tumor tissues.14-18 Through the process known to be “Enhanced Permeability and Retention (EPR) effect, they are extravasated into tumor tissues for prolonged blood circulation.19-21 Once the nanocarriers are internalized into cancer cells through endocytosis, the encapsulated drugs can be released from the nanocarriers.22 A number of ABP-based self-assembled nanocarriers have been developed and effective systems rely on the choice of building blocks, particularly hydrophobic blocks, to synthesize novel ABPs. Polylactide (PLA) belongs to a class of hydroxyalkanoic acid-based hydrophobic aliphatic polyesters, along with polycaprolactone (PCL) and polyglycolide (PGA). PLA and its copolymers are biocompatible and FDA-approved for clinical use. They are slowly degraded by hydrolysis or enzymatic reaction in physiological conditions to the corresponding water-soluble oligomers and lactic acids. In mammalian physiology, lactic acid is naturally produced as a by-product of anaerobic respiration (a form of respiration using electron acceptors other than oxygen). It is then metabolized into carbon dioxide and water. These unique features have made PLA-based materials valuable for extensive applications in biomedical fields, including sutures, bone fixation implants, and stents as well as tissue scaffolds and drug delivery carriers.23-26 Toward the successful biomedical applications of conventionally-designed PLA and PLA-based nanomaterials, a critical challenge to be addressed is associated with the slow biodegradation of PLA and thus slow and uncontrolled release of encapsulated drugs. Such slow release is attributed to delayed diffusion through the hydrophobic PLA ACS Paragon Plus Environment

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core due to both hydrophobic interactions as well as the slow hydrolysis of the ester linkages of the PLA backbones. An introduction of stimuli-responsive degradation (SRD) into the design of novel PLA-based ABPs has been explored as a promising platform enabling the controlled/enhanced release of encapsulated therapeutics for cancer therapy. This review summarizes the recent development of novel PLA-based ABPs and their selfassembled nanostructures for SRD-induced enhanced drug release, with a focus on their design, synthesis, and evaluation as intracellular drug delivery nanocarriers. Further, conventional PLA and PLA-based ABP assemblies as well as general concept and typical strategies of SRD are described in this review.

2. Conventional PLA and PLA-based ABP assemblies 2.1. Synthesis and properties of PLA As illustrated in Figure 1, well-controlled PLA with narrow molecular weight distribution is generally synthesized by ring opening polymerization (ROP) of lactide (LA) in the presence of hydroxyl (OH) or amine (NH2)-bearing initiators at elevated temperatures.27, 28. The fundamentals and kinetics of ROP of cyclic monomers including LA are described in literature.25, 29-32 Furthermore, recent reports describe elegant strategies that allow for the synthesis of a variety of functional PLAs. Interesting strategies utilize functional LA monomers bearing vinyl/then azide group33 as well as functional initiators bearing disulfide,34 pyridiyl disulfide,35 and a peptide linkage with a sequence of Pro-Leu-Gly-Leu-Ala-Gly.36, 37 Given stereospecific characteristics, PDLA from D-LA and PLLA from L-LA are semi-crystalline with a melting transition (>150 °C), while PDLLA from DL-LA is amorphous with a glass transition at ≈45 °C. Hereinafter, note that “PLA” presents amorphous PDLLA. Both PDLA and PLLA have great mechanical properties due to the presence of crystalline domains. Furthermore, PDLA and PLLA form physically-crosslinked networks through stereocomplexation. Such feature has been explored for supramolecular micellization for drug delivery.38, 39 R-OH Sn(Oct)2 LA

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Figure 1. ROP of LA to synthesize PLA. ACS Paragon Plus Environment

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2.2. General strategies to PLA-based ABPs and their assemblies One of the challenges for clinical uses of PLA involves its hydrophobicity that causes short residence time in blood by undesired elimination through opsonization. The hydrophobicity of PLA also presents its incompatibility with biological systems, leading to decreased therapeutic efficacy. Significant efforts have been made over the past years to address the challenge of hydrophobicity of PLA. A promising solution is to introduce water-soluble or hydrophilic blocks into the design of PLAcontaining ABPs. Typically-explored hydrophilic blocks include poly(ethylene glycol) (PEG), poly(amino acid)s, polysaccharides, and polymethacrylates. The resultant ABPs tend to self-assemble toward micellar aggregation in aqueous solution, consisting of hydrophobic PLA block residing in core and hydrophilic block forming outstretched coronas (Figure 2). The development of PLA-based ABPs and their self-assembled structures is summarized in a review article.40 This section describes recent strategies to synthesize PLA-based ABPs, particularly with PEG and polypeptide, since 2010. PEG is FDA-approved and has been extensively used as a hydrophilic polymer in biomedical field. A general approach to synthesize PLA-based PEG block copolymers involves the direct ROP of LA in the presence of PEG as an initiator. Various PEG initiators have been examined to synthesize novel copolymers. They include a monofunctional methoxy PEG having a terminal OH group (mPEG-OH) for the synthesis of mPEG-b-PLA diblock copolymer, a difunctional PEG having both terminal OH groups (HO-PEG-OH) for PLA-PEG-PLA triblock copolymer, and multifunctional PEGs for highlybranched copolymers.41-45 Synthetic polypeptide based on amino acid or poly(amino acid) is biocompatible and biodegradable.46 Most diblock copolymers consisting of PLA and poly(amino acid) blocks have been synthesized by ROP of an α-amino acid N-carboxyanhydride from NH2-terminated polymer, followed by the hydrolysis for deprotection of groups to the corresponding amino acids. A diblock copolymer of PLA-b-poly(L-lysine) was synthesized by ROP of N-carbonylbenzoxy-L-lysine in the presence of NH2-PLA initiator.47 The synthesis of a triblock copolymer of PEG-b-poly(L-serine) grafted with PLA has been reported. The approach involves the ROP of o-(t-butyl)-L-serine in the presence of PEG-NH2 and following hydrolytic cleavage of pendant t-butoxy groups to the corresponding OH groups. The resultant PEG-b-P(L-serine) was used as a macroinitiator for the ROP of LA, yielding the designed product.48


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Figure 2. Schematic illustration of conventionally-designed PLA-based ABPs with hydrophilic blocks such as PEG, poly(amino acid), polysaccharide, and polymethacrylate (a) and their self-assembly to form micellar aggregates with PLA cores surrounded with hydrophilic coronas (b).

3. Stimuli-responsive degradation (SRD) for enhanced release 3.1. General concept of SRD Stimuli-responsive (or smart) (co)polymers undergo a chemical or physical transition in response to external stimuli (or triggers).49-52 Most of these transitions, particularly utilized in biological and biomedical applications, result in a change in hydrophobic/hydrophilic balance of the smart polymers. Physical transition causes a volume change through either a coil-globular or conformational transition when physical stimuli are applied. Of physical stimuli including pH, magnetic, and electric fields, a typical example is temperature change. Poly(N-isopropyl acrylamide) (PNIPAM) is a typical thermoresponsive polymer. It undergoes coil-globular transition at lower critical solution temperature (LCST).53-55 At below LCST, PNIPAM is hydrophilic and becomes soluble in water; however, it turns to be hydrophobic, forming aggregates, at above LCST. Due to such temperature-responsive transition, PNIPAM-based block copolymer nanoassemblies have been extensively utilized for drug delivery exhibiting a size-controlled drug release.


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In contrast, chemical transition involves the degradation (or disintegration) through the cleavage of dynamic (or labile) covalent bonds in the presence of chemical or biological stimuli such as glutathione, acidic pH, light, or enzyme.56-60 Such chemical transition is known to be “stimuliresponsive degradation (SRD)”, which involves the introduction of cleavable linkages (dynamic covalent bonds) into the design of nanomaterials, particularly self-assembled ABP-based micellar nanoaggregates. Later, these labile linkages are cleaved in the presence of chemical and biological stimuli when needed. Consequently, the SRD property allows for controlled/enhanced release of encapsulated drugs from drug-loaded nanocarriers. It is ideal when dynamic linkages are cleaved in response to biological components of targeted cells or tissues. As summarized in Figure 3, the promising dynamic linkages include reduction-responsive disulfides;61-64 acid-labile linkages such as acetals, ketals, orthoesters, hydrazones, and imines;65, 66 and enzyme-responsive linkages such as specific peptide linkages, ester, and amide bonds;67-69 as well as photo-cleavable linkages such as coumarin dimers, pyrenylmethyl and o-nitrobenzyl group.70-72 Disulfide linkages are cleaved to the corresponding thiols in reducing environments. In biological systems, glutathione (GSH, a tripeptide containing cysteine) is found at a higher concentration in intracellular environments (≈10 mM) than extracellular environments (≈10 µM), and even at elevated levels in cancer cells.73, 74 Covalent ester linkages in the presence of esterase enzymes and specific peptide linkages are cleaved by enzymatic reactions. Similarly, acid-labile linkages are cleaved in acidic conditions. In biological systems, acidic pH is presented in tumor tissue (pH = 6.5-6.9) as well as in endosomes and lysosomes (pH = 5.0-6.5). Photo-labile linkages are cleaved on demand upon irradiation with light at targeted sites. It is imperative that drug-loaded nanocarriers are able to release encapsulated anticancer drugs in a rapid and controlled fashion after being taken up by cancer cells after extravasation into tumor tissues from blood circulation. Self-assembled nanocarriers designed with cleavable linkages are stable under physiological conditions; however, they can be dissociated in a controlled fashion as cellular components are provided appropriate stimuli in tumor tissues or cancer cells. Consequently, SRD has been extensively explored as a promising platform in the design and development of a variety of SRDexhibiting block copolymers and their self-assembled nanostructures for tumor-targeting drug delivery applications.75-78


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Figure 3. Dynamic linkages including reduction, enzyme, and acidic pH-responsive cleavable as well as photo-labile linkages.

3.2. General approaches to SRD-exhibiting ABPs and their assemblies Figure 4 summarizes the general approaches that allow for the synthesis of SRD-exhibiting block copolymers and their self-assembled nanostructures, which are based on the number, position, and location of single or multiple (or dual) cleavable linkages.79, 80 Figure 4a illustrates “single location SRD approach (SL-SRD)”. Four distinct strategies can be categorized with the number and position of the cleavable linkages in single locations, as in micellar cores or at core/corona interfaces of selfassembled micelles. They respond to either single stimulus or multiple stimuli. Pendant multicleavable ABPs are designed with multiple linkages positioned in the pendent chains of hydrophobic blocks (strategy A). Backbone multi-cleavable ABPs have multiple cleavable linkages positioned on the main chains of hydrophobic blocks (strategy B). Typical examples of backbone multi-cleavable blocks include step-growth polymers, typically polyesters labeled with disulfides81, 82 as well as polyurethanes with o-nitrobenzyl83 and SeSe linkages.84 Mono-cleavable ABPs involve single cleavage linkages in the middle of single triblock copolymers (strategy C).85, 86 The strategies A, B, and C feature the position of cleavable linkages in hydrophobic cores of self-assembled micelles. In response to external stimuli, the pendant multi-cleavable micelles (strategy A) are disintegrated (or destabilized) ACS Paragon Plus Environment

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by a change of hydrophobic/hydrophilic balance upon the cleavage of pendant cleavable linkages. Other micelles (strategy B and C) are dissociated by main chain degradation upon the cleavage of cleavable linkages positioned on backbones. Strategy D involves the synthesis of ABPs with cleavable linkages at the junction of hydrophilic and hydrophobic blocks. These Strategy D ABPs self-assemble to form micelles with cleavable linkages positioned at the interfaces of hydrophobic cores and hydrophilic coronas. In the presence of triggers, hydrophilic coronas are shed from the micellar cores upon cleavable linkages at the interfaces (thus, called sheddable micelles). For the preparation of reduction-responsive disulfide-containing ABPs, typical examples of pendant multi-cleavable hydrophobic blocks include polymethacrylates having pendant alkyl disulfide87, 88 or pyridiyl disulfide groups.89-91 The design of these ABPs presents an additional benefit that allows for the synthesis of disulfide-induced core crosslinked micelles (CCMs). The pendant disulfides are further involved in in situ disulfide-thiol exchange crosslinking reactions in micellar cores when being treated with a residual reducing agent. The resulting disulfide-CCMs exhibit enhanced colloidal stability during blood circulation and endocytosis92, 93 as well as reductionresponsive enhanced release of encapsulated drugs.94-96 Dual location SRD (DL-SRD) approach centers on the synthesis of new intracellular nanocarriers having disulfide linkages in dual locations (Figure 4b). The locations of the disulfides can be in the micellar core, in the interlayered corona, or at the core/corona interface. The placement of reductionresponsive linkages in dual locations provides desirable synergistic release kinetics and therapeutic effects. Recent examples include novel ABP nanoassemblies having disulfides at core/interface and core/interlayered corona.97, 98 As illustrated in Figure 4c, multiple location multiple SRD (ML-MSRD) approach has been exploited to develop new intracellular nanocarriers possessing multiple stimuli-responsive cleavable linkages at multiple or dual locations. This new route offers considerable versatility in respect that responses to each stimulus can independently and precisely regulate drug release at several locations. A few reports describe dual systems such as reduction (interface)/pH (core)99, 100 and pH (interface)/reduction (core),101 and reduction (interface)/light (core).102


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Figure 4. General approaches to synthesize SRD-exhibiting block copolymers and their self-assembled nanostructures as single location (a), dual location SRD (b), and multiple location multiple SRD (c) approaches.

4. Strategies to reduction-responsive PLA-based ABP systems 4.1. Direct polymerization strategy This direct polymerization strategy begins with the design and synthesis of multifunctional initiators bearing three distinct functional groups: one for ROP of LA, the other for controlled/living radical polymerization, and a disulfide linkage for reduction-responsive degradation. In the presence of the initiators, the sequential polymerizations allowed for the formation of PLA-based ABP functionalized with disulfide linkages. As a consequence, this strategy enables to overcome the complexity caused by the covalent coupling strategy (described in the next section) that requires extra separation steps of excess homopolymers from targeted PLA-based ABPs. One elegant approach involves the synthesis of sheddable ABPs and their nanoassemblies. As summarized in Figure 5, this approach centers on the synthesis of a double-head initiator of HO-SS-Br ACS Paragon Plus Environment

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by a facile coupling reaction of 2-hydroxyethyl disulfide with α-bromoisobutyryl bromide. The initiator was used to initiate the ROP of LA catalyzed with tin(II) 2-ethylhexanoate (Sn(II)EH2) in toluene at 120 °C, yielding well-defined PLA-SS-Br homopolymers with narrow molecular weight distribution as Mw/Mn < 1.0. The detailed studies indicate that initial mole ratio of [Sn(II)EH2]0/[HOSS-Br]0 and polymerization time are important parameters that significantly influence low and high molecular weight PLA-SS-Br synthesis.103, 104 Next, atom transfer radical polymerization (ATRP) was employed for various hydrophilic methacrylate monomers in the presence of the PLA-SS-Br macroinitiator to synthesize a variety of novel PLA-SS-based ABPs bearing a disulfide linkage at the block junction between PLA and polymethacrylate. These ABPs formed sheddable micelles having disulfides at PLA core/corona interfaces.

Figure 5. Synthetic route to a double-head initiator of OH-SS-Br for both ROP of LA and ATRP of methacrylates, well-controlled PLA-SS-Br by ROP of LA, and PLA-SS-based ABPs by ATRP in the presence of PLA-SS-Br macroinitiator.

A report describes the synthesis of PLA-SS-based poly(quarternized N,N-dimethylaminoethyl methacrylate (PcDMA). The resultant PLA-SS-PcDMA self-assembled to form PLA cores, encapsulating anticancer drugs, surrounded with PcDMA cationic coronas, enabling the formation of complementary complexes with nucleic acids. Such sheddable-type micelloplexes exhibit enhanced release of both anticancer drugs and nucleic acids upon reductive response, suggesting great potential for dual chemotherapy and gene therapy.105 Other reports also describe the synthesis of PLA-SS-based ACS Paragon Plus Environment

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poly(oligo(ethylene oxide) monomethyl ether methacrylate)106 and poly(aminoethyl methacrylate)/2,3dimethylmaleic anhydride107 for drug delivery. Further, the DL-SRD approach was explored to synthesize a new PLA-SS-based triblock copolymer possessing disulfide linkages at dual locations, thus PLA-SS-PHMssEt-b-POEOMA. As illustrated in Figure 6, the self-assembly of the triblock copolymer allowed for the formation of micellar aggregates having multiple pendant disulfide linkages in a hydrophobic interlayer as well as single disulfides at interfaces of the interlayer and PLA core, surrounded with hydrophilic coronas. Through thiol-responsive cleavage of these dually located disulfide linkages, novel interlayercrosslinked micelles with a crosslinkable and sheddable extended corona were formed, thus combining enhanced colloidal stability, along with controlled release of encapsulated anticancer drugs to promote the inhibition of cell proliferation after internalization into cancer cells.108

Figure 6. Schematic illustration of synthesis of PLA-SS-based interlayered crosslinked micelles for enhanced colloidal stability and shedding extended coronas for rapid release of encapsulated anticancer drugs, based on PLA-SS-PHMssEt-b-POEOMA triblock copolymers having multiple pendant disulfides in the interlayer and single disulfides at junctions of PHMssEt and POEOMA blocks in aqueous solution.108 Copyright 2013 Royal Society of Chemistry.

Another approach involves the synthesis of PLA-based mono-cleavable and dual location SRDexhibiting ABPs and their nanoassemblies. As illustrated in Figure 7, this approach began with the ACS Paragon Plus Environment

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synthesis of functional PLA having a disulfide in the center (OH-PLA-SS-PLA-OH, i.e. SS(PLA-OH)2) by ROP of LA in the presence of 2-hydroxyethyl disulfide. For the synthesis of mono-cleavable SS(PLA-b-POEOMA)2 triblock copolymer, ATRP of OEOMA was followed by the esterification of the resultant SS(PLA-OH)2 to SS(PLA-Br)2. At concentrations above the CMC (5 µg/mL), this monocleavable ABP formed self-assembled micellar aggregates with disulfide-containing PLA cores. Thioltriggered degradation exhibit enhanced release of encapsulated anticancer drug; however, thiolresponsive drug release kinetics was slower, compared to multi-cleavable ABP systems. Such slow release from mono-cleavable micelle systems is presumably attributed to the amphiphilicity of the degraded products (HS-PLA-b-POEOMA and HS-PLA-b-PEG) with a half of molecular weight of their original ABPs (i.e. SS(PLA-b-POEOMA)2 and SS(PLA-SS-PEG)2). These degraded products appeared to form smaller-sized aggregates which can also encapsulate drugs released from original mono-cleavable micelles.109 In addition to the combination of ROP and ATRP, the combined ROP and esterification has been also explored to synthesize a triblock copolymer containing PLA and PEG, thus SS(PLA-b-PEG)2.110, 111 To explore a DL-SRD, a novel triblock copolymer having triple disulfide linkages in the center and at the junction of PLA and POEOMA blocks (SS(PLA-SS-POEOMA)2) was synthesized by a combination of facile coupling reactions and ATRP from SS(PLA-OH)2. As illustrated in Figure 8, the ABP enabled the formation of micelles with disulfides positioned both in the hydrophobic PLA core and at the core/corona interface. The reductive response to glutathione as a cellular trigger resulted in the cleavage of the disulfide linkages both at the interface shedding hydrophilic coronas as well as in the PLA core causing disintegration of PLA cores. Such dual disulfide degradation process led to a synergistically enhanced release of encapsulated anticancer drugs in cellular environments.112


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Figure 7. Synthetic routes to novel PLA-based mono-cleavable and dual location SRD-exhibiting ABPs functionalized with disulfide linkages.

Figure 8. For SS(PLA-SS-POEOMA) triblock copolymer, reduction-responsive cleavage of disulfides in the presence of DL-dithiothreitol (a), dynamic light scattering diagrams and transmission electron microscopy images of the micelles before and after treatment with 10 mM GSH at 1.2 mg/mL (b), and enhanced release of DOX from DOX-loaded micelles in the absence (control) and presence of 10 mM GSH (c).112 Copyright 2014 American Chemical Society.


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4.2. Covalent coupling strategy This strategy utilizes facile coupling reactions of functional PLA and hydrophilic polymer, either of which contains disulfide groups, thus yielding reduction-responsive PLA-based ABPs. One of the drawback of this strategy involves the extra separation steps to remove excess homopolymers from targeted ABPs because it requires the use of excess of either PLA or hydrophilic polymer. A report describes the reaction of poly(2-ethoxy-2-oxo-1,3,2-dioxaphospholane) (PEP) synthesized by ROP of EP with 3,3’-dithiodipropionic acid. The formed PEP-SS-COOH was then coupled with a hyperbranched Bolton H40-PLA-OH to yield H40-star-PLA-SS-PEP.113 Other reports describe the synthesis of D-α-tocopherol (TPGS)-conjugated PEG-SS-PLA114 and folate-conjugated PEG-PLA-SSpolyethyleneimine (PEI).115 The formed PLA-based ABPs having disulfide linkages at the block junctions allowed for the formation of sheddable micelles having disulfide linkages located at hydrophobic PLA cores/coronas (SL-SRD). Another approach shown in Figure 9 involves the synthesis of a folic acid-conjugated triblock copolymer comprising of PEG and PLA with multiple disulfide linkages (PEG-SS-PLA-SS-PLA-SSPEG-folate) by multiple steps of coupling reactions (DL-SRD). Through nanoprecipitation method of the copolymer, redox-responsive folic acid and trastuzumab functionalized polymersomes with diameter = 150 nm were formed, with disulfides in the PLA cores and at core/corona interfaces. The presence of multiple redox responsive disulfide linkages led to complete disintegration of polymersomes in redox rich environment of cancer cells resulting in enhanced doxorubicin release. Folic acid and trastuzumab mediated active targeting resulted in improved cellular uptake and enhanced apoptosis in vitro studies. Further, in vivo studies in Ehrlich ascites tumor bearing Swiss albino mice exhibit enhanced antitumor efficacy and minimal cardiotoxicity of polymersomes.116


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Figure 9. Schematic illustration of redox-responsive biodegradable polymersomes comprising of PEGSS-PLA-SS-PLA-SS-PEG-folate triblock copolymer with multiple disulfide linkages as intracellular drug delivery nanocarriers in breast cancer.116 Copyright 2015 American Chemical Society.

Shen and coworkers have reported an interesting approach that involves reversible and unsymmetrical disulfide bond formation directed by hydrogen bonding association. Consequently, this strategy requires the synthesis of functional homopolymers with oligoamide strands having complementary H-bonding sequences (i.e. arrays of H-bond acceptor and donor). As illustrated in Figure 10, PEG and PLA chains were end-modified with amide units A and B which are hydrogen bonding donor and acceptor. Further, they were functionalized with S-trityl groups capable for the formation of a double disulfide linkage by oxidation. The resultant PEG-A and PLA-B treated with iodine resulted in connection of PEG and PLA blocks, yielding PEG-SS-PLA diblock copolymer, while minimizing self-coupling. The resulting diblock copolymer self-assembled to form sheddable micelles having unsymmetrical disulfide linkages at PLA core/PEG corona interfaces. When the selfassembled micelles were treated with DTT, they were dissociated to PLA and PEG chains in aqueous solution.117 Further, this disulfide and supramolecular H-bonding strategy has been explored to synthesize novel block copolymers and their nanoassemblies. They include PEG-SS-PLA-SS-PEI triblock copolymer for gene delivery118 as well as PEG-grafted chitosan oligosaccharide,119 PLA-SSPEG-SS-PLA triblock,120 and (PLA-SS-PEG) multi-block copolymer121 for drug delivery.


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Figure 10. Schematic illustration of the strategy to synthesis, micellization, and redox responsiveness of a PEG-PLA diblock copolymer (a) and coupling of PEG-A and PLA-B based on unsymmetrical, reversible disulfide-bond formation instructed by H-bonding (b).117 Copyright 2014 American Chemical Society. 4.3. Drug-polymer conjugation strategy This strategy (called polymer prodrug strategy) involves the conjugation of anticancer drug molecules to PEG-b-PLA block copolymer through disulfide linkages via multiple steps of organic coupling reactions. The drug molecules were conjugated to PLA blocks of the copolymers, thus yielding reduction-responsive PEG-b-PLA-drug conjugates (i.e. prodrugs). Due to the amphiphilicity, these prodrugs self-assemble to form drug-conjugated nanoassemblies. After extravasation into tumor tissues and further internalization into cancer cells, anticancer drugs can be released from these prodrugs upon the cleavage of disulfide linkages in a reducing environment. Reports describe the synthesis and reduction-responsive drug release of curcumin-conjugated PLA-b-PEG prodrug (CurSS-PLA-b-PEG)122 and docetaxel-conjugated poly(lactide-co-glycolide)-b-PEG (DTX-SS-PLGA-bPEG)123 and its self-assembled micellar aggregates.


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5. Strategies to acidic pH-responsive PLA-based ABP systems Inherently, PLA slowly degrades to the corresponding oligomers or LA species through the cleavage of backbone ester groups in a physiological condition. This hydrolysis process can be promoted in acidic conditions. Such process called acidic hydrolysis can facilitate the degradation process of PLA-based nanoparticles, inducing the enhanced release of encapsulated drugs. Further to enhance the degradation kinetics, several approaches have been proposed to synthesize acidic pHresponsive PLA-based nanoassemblies. 5.1. Sheddable and prodrug strategies For the strategy to develop PLA-based sheddable systems, acidic pH-cleavable covalent tetrahydropyran (THP) chemistry was explored for the synthesis of PEO-THP-PLA block copolymer.124 The copolymer self-assembled to form micellar aggregates having THP linkages at the interfaces of PLA cores and PEG coronas. In acidic pH, THP linkages were cleaved at the interfaces. The process enabled shedding PEG coronas from PLA cores, leading to enhanced release of encapsulated Dox. In addition, the preparation of pH-responsive nanoparticles having covalent phenylboronic-catechol ester linkages at the interfaces of PLA cores with poly(ethyleneimine) coronas was reported.125 More interestingly, supramolecular host-guest chemistry was employed for the design of sheddable PLA systems. As illustrated in Figure 11, terminal benzimidazole-functionalized PEG (PEG-BM) and terminal β-cyclodextrin-functionalized PLLA (PLA-CD) were synthesized. Supramolecular self-assembly of these polymers enabled the formation of colloidally-stable aggregates having supramolecular CD-BM linkages at the interfaces of PLA cores and PEG coronas. TEM analysis indicates the diameter = 274 nm for the aggregates prepared at pH = 7.4. As pH decreased to 5.5, the diameter by TEM increased to 590 nm, due to pH-responsive dissociation of supramolecular CD-BM linkages. Such acidic pH response allows for enhanced release of encapsulated Dox, confirmed by in vitro and in vivo studies.126


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Figure 11. Synthesis (a) and intracellular delivery (b) of Dox-loaded PEG-BM/CD-PLLA supramolecular aggregates exhibiting triggered release of encapsulated Dox in response to intracellular microenvironment.126 Copyright 2015 American Chemical Society.

For the strategy to develop acidic pH-responsive prodrugs, various anticancer drugs have been conjugated covalently through acidic pH-cleavable linkages with PLA-based ABPs as multiple steps of organic coupling reactions have been employed. Due to amphiphilic nature, the resultant ABP-drug conjugates self-assembled to form nanoassemblies containing drugs covalently conjugated to hydrophobic cores. Upon the cleavage of pH-responsive linkages, anticancer drugs were released from nanoassemblies. Reports describe the synthesis of “linear” PLA-drug conjugates by simple conjugation of drugs with terminal PLA blocks of PLA-b-PEG, typically Dox conjugated with acetal linkage127 and docetaxel conjugated with hydrazone linkage.128 Other reports also describe the synthesis of “grafted” PLA-drug conjugates (PLA-graft-drug conjugates) by conjugation of drugs such as particularly Dox with pendant functional groups on PLA backbones through acid pH-cleavable linkages such as hydrazones. Yu and coworkers have reported the synthesis of amphiphilic PLAs grafted with Dox and PEG pendants (PLA-graft-Dox-PEG).129 As illustrated in Figure 12, the synthetic route involves 1) ring opening polymerization to synthesize PLA functionalized with alkyne pendants (PLA-alkyne), 2) alkyne-azide cycloaddition to conjugate PEG-N3 and 6-azidohxyl-4-formylbenzoate, and 3) coupling reaction of Dox with the aldehyde groups through hydrazone linage formation. Similarly, Ganivada et al have synthesized PEG-based PLA/polycarbonate copolymer that has biotin conjugated to PEG and pendant Dox grafted to polycarbonate through hydrazone linkages.130 Initially, biotin-labeled PEG (biotin-PEG) and a cyclo-carbonate monomer functionalized with di-alkynes were synthesized by ACS Paragon Plus Environment

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coupling reactions. Then, a ROP of LA and the monomer in the presence of biotin-PEG allowed for the synthesis of biotin-labeled PEG-b-(PLA-co-polycarbonate) with pendant alkynes. Their alkyneazido cycloaddition with azido-functionalized Dox was followed.

Figure 12. Synthesis of PLA-graft-Dox-PEG.129 Copyright 2015 Royal Society of Chemistry.

5.2. Strategy to acidic pH-responsive volume change This strategy involves the introduction of acidic pH-responsive groups such as β-amino ester (AE), oxazoline, and histidine into the design of PLA-based ABPs.131-135 Upon change to acidic environments, these groups induce the assemblies undergoing changes in their polarities and eventually their volumes or dimensions, leading to enhanced release of encapsulated drugs. Zhang et al has reported the synthesis and acidic pH responsive drug release of poly(β-amino ester) (PAE)-based ABP, thus (PEO-b-P(PLA-co-PAE), by copolymerization of 4,4’-trimethylene (TDP) with vinylfunctionalized PLA and PEO through a Michal-addition reaction of diamines to vinyl groups.131 PAE is soluble at pH 6.5 because of its tertiary amine with pKb = 6.5. At a physiological pH, the ABP assembled to form Dox-loaded nanoassemblies consisting of (PLA-co-PAE) cores surrounded with PEO coronas. At mild acidic pH (5.0-6.5), the polarity of hydrophobic PLA cores could be changed to be relatively hydrophilic due to protonation of PAE groups. This process caused the loss of integrity of the formed nanoaggregates, exhibiting sustainable release of encapsulated Dox. Qiao and coworkers have reported the synthesis of a triblock copolymer consisting


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of PEG, PLA, and poly(L-histidine) blocks, thus PEG-b-PLA-b-PHis, with different degrees of polymerization of PLA and Phis blocks.132 At pH = 8.5, the ABP formed micellar aggregates consisting of (PLA-b-PHis) cores surrounded with PEG coronas. Upon a change of pH to 4.5, PHis blocks were protonated, which resulted in reassembly of the micellar aggregates into micelles of PLA cores and PEG and protonated Phis coronas. Such pH-induced reassembly triggered enhanced release of encapsulated Dox, confirmed by cytotoxicity and CLSM results. In addition, reports describe the preparation of acidic pH-responsive nanoassemblies through co-micellization of acidic pH-responsive ABP with peptide-conjugated PEG-b-PLA for drug delivery with active targeting to specific tumors.134, 135

6. Intracellular tumor-targeting drug delivery Most PLA-based ABP micelles having SRD elements, particularly disulfides and acidic pH-labile groups, have been designed with hydrophilic coronas, typically PEG or POEOMA. They are nontoxic to mammalian cells, and thus biocompatible. Anticancer drugs such as doxorubicin (Dox) and paclitaxel were encapsulated physically in hydrophobic PLA cores. The resultant drug-loaded SRDexhibiting micelles were degraded or disintegrated upon the cleavage of the cleavable linkages in response to glutathione or acidic pH (5-6.5). Such SRD enabled the enhanced release of encapsulated drugs. Drug-loaded PLA-based micelles exhibiting SRD-induced enhanced drug release were further evaluated as effective intracellular drug delivery nanocarriers for cancer therapy. In vitro intracellular trafficking of drugs from the micelles were studied using flow cytometry and confocal laser scanning microscopy (CLSM). As an example, Dox-loaded micelles from POEOMA-SS-PLA-SS-PLA-SSPOEOMA triblock copolymer were incubated with HeLa cancer cells.112 As illustrated in Figure 13, compared with HeLa cells, the flow cytometric histogram of HeLa cells incubated with Dox-loaded micelles presented a noticeable shift in the direction of high fluorescence intensity. CLSM images also show that HeLa cells incubated with Dox-loaded micelles display strong Dox fluorescence in their nuclei. These results confirm that Dox-loaded micelles enable the delivery and release of Dox into nuclei of cancer cells.


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Figure 13. Flow cytometric histograms (a) and CLSM images (b) of HeLa cells only (A) and incubated with DOX-loaded micelles of POEOMA-SS-PLA-SS-PLA-SS-POEOMA triblock copolymer (B), and free DOX (C) for 16 hrs. Scale bar = 20 µm.112 Copyright 2014 American Chemical Society.

Further to in vitro studies, reductive PLA-based micelles were evaluated in vivo (animal models).114, 116, 118, 136 Typically, a report describes the synthesis of hyaluronic acid-cystamine-PLGA block copolymer (HA-SS-PLGA) and self-assembly to construct sheddable micelles encapsulated with both Dox) and cyclopamine (CYC, a primary inhibitor of the hedgehog signaling pathway of cancer stem cells).137 Dual drug-loaded particles potently diminished the number and size of tumorspheres and HA showed a targeting effect towards breast CSCs. As illustrated in Figure 14, in vivo combination therapy further demonstrated a remarkable synergistic anti-tumor effect and prolonged survival compared to mono-therapy using the orthotopic mammary fat pad tumor growth model. The codelivery of drug and the CSC specific inhibitor towards targeted cancer chemotherapeutics provides an insight into anticancer strategy with facile control and high efficacy.


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Figure 14. For Dox-loaded micelles self-assembled from hyaluronic acid-cystamine-PLGA block copolymer (HA-SS-PLGA), in vivo combination therapy using orthotopic mammary fat pad tumor growth model; tumor volumes (A, B, D), life survival of tumor-bearing mice (C), photos of excised tumors at the end of the treatment at day 40 (E), and day 75 (F).137 Copyright 2015 Royal Society of Chemistry.

An interesting study has been reported for different intracellular drug delivery routes of selfassembled and disulfide bonded micelles using physically loading hydrophobic FRET probes (Figure 15). The former was made of mPEG-b-PLA (no disulfide), while the latter was made of mPEG-(Cys)4PLA block copolymer synthesized by coupling reaction of oligocysteine (Cy4) with PEG and PLA blocks. The self-assembled micelles were structurally dissociated by micelle–membrane interactions, and the hydrophobic probes were distributed on the plasma membrane. However, intact disulfide bonded micelles carrying hydrophobic probes were internalized into cancer cells via multiple endocytic pathways. Following internalization, disulfide bonded micelles were decomposed in early endosomes by glutathione-mediated disulfide bond reduction, exposing the probes to intracellular organelles.138 Further, disulfide bonded micelles stably retained doxorubicin in the bloodstream and efficiently delivered the drug to a tumor, with a 7-fold increase of the drug in the tumor and 1.9-fold decrease in the heart, as compared with non-crosslinked self-assembled micelles. With a Dox dose as low as 2 mg/kg, disulfide bonded micelles almost completely suppressed tumor growth in mice.139


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Figure 15. Schematic diagram of cellular entry routes and intracellular fates of self-assembled mPEGb-PDLLA micelles and disulfide bonded mPEG-(Cys)4-PLA micelles.

7. Summary and outlook The recent advance in the development of PLA-based ABPs and their self-assembled nanostructures exhibiting SRD-induced enhanced drug release is summarized, with an emphasis of their design, synthesis, and evaluation as intracellular drug delivery nanocarriers for cancer therapy. Several novel strategies have been reported to synthesize various self-assembled stimuli-responsive degradable PLA-based micellar aggregates having the different numbers, positions, and locations of single or multiple (or dual) cleavable linkages, particularly disulfide and acid-labile linkages. Covalent coupling, direct polymerization, and drug-polymer conjugation strategies to synthesize reductionresponsive PLA-based nanoassemblies as well as sheddable and prodrug stategies to acidic pHresponsive PLA-based nanoassemblies have explored. Most of these PLA-ABPs were designed with dsulfide and acid-liable linkages positioned in the juctions of PLA and hydrophilic blocks or PLA and drug, in the center of triblock copolymers, or in teh dual locations. Further to SRD-induced enhanced/controlled release profiles of encapsulatd drugs to kill cancer cells, in vitro (cells) and in vivo studies suggest that the development of novel SRD-exhibiting PLA-based nanoassemblies is the ACS Paragon Plus Environment

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promising platfrom for tumor-targeting drug delivery. Current and future design and development of more effective SRD PLA-based nanoassemblies require a high degree of control to their degradation kinetics for precise release of encapsulated anticancer drugs. Further to the design and development of new nanoassemblies, more efforts should be made to in vivo and clinical studies.

Acknowledgements Financial supports from Canada Research Chair (CRC) Award and NSECR Discovery Grant in Canada are greatly acknowledged. JKO is a Tier II CRC in Nanobioscience.

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Graphic abstract


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Stimulus-Responsive Degradable Polylactide-Based Block Copolymer

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